10,11-DIHYDRO-,9,10-DIHYDRO-10,10-DIMETHYL-5-OR 9-{8 3-AMINO-2-oxo -OR-HYDROXY-PROPYLIDENE{9 {11 -5H-DIBENZO{8 a,d{9 {11 CYCLOHEPTENES AND-ANTHRACENES

ABSTRACT

The products are new tricyclic amino compounds and acid addition salts thereof, said tricyclic amino compounds corresponding to the general formula : WHERE X represents one of the following divalent hydrocarbon radicals : A represents a carbonyl (CO) or a hydroxymethylene (CHOH) group and R represents a monoalkylamino or a dialkylamino radical. They are very useful substances for human therapeutics, namely as antidepressants and antianxiety agents. The process for preparing compounds of formula (1) and their salts is disclosed.

United States Patent Boissier et al.

[451 July 4,1972

[72] Inventors: Jacques Robert Boissier, Paris; Roger Ratouis, Saint-Cloud, both of France Societe Anonymedite: Roussel-UCLAF, Paris, France 221 Filed: March 3,1969

21 Appl.No.: 804,024

[73] Assignee:

[52] US. Cl. ..260/50l.l2, 260/501 .18, 260/5705 C, 260/5706, 260/5708 TC, 260/583 H, 424/330 [51] Int. Cl ..C07c 91/02, C070 97/10 [58] Field of Search ..260/570.8 TC, 570.5 C, 570.6, 260/501.l2, 501.18

[56] References Cited UNITED STATES PATENTS 3,202,686 8/1965 Hughes et al. 3,281,469 10/1966 Peters et al. ..260/570.8 3,215,739 11/1965 I-Iolm ..260/570.8

OTHER PUBLICATIONS Royals, Advanced Organic Chemistry, pages 529- 530 (1954) Wagner et al., Synthetic Organic Chemistry, pages 149- 150 and 340- 341 (1963) Hines; Robert V.

Primary Examiner-Robert V. Hines Hines Attorney-Davis, I-Ioxie, Faithful] & Hapgood [57] ABSTRACT The products are new tricyclic amino compounds and acid addition salts thereof, said tricyclic amino compounds corresponding to the general formula where X represents one of the following divalent hydrocarbon radicals:

HgC CH3 CH;CH CH=CH- or c- A represents a c ai onyl 6 (CHOI-I) group and R represents a monoalkylamino or a dialkylamino radical.

They are very useful substances for human therapeutics, namely as antidepressants and antianxiety agents.

The process for preparing compounds of formula l and their salts is disclosed.

5 Claims, No Drawings 10,1 l-DIHYDRO-,9,1 O-DIHYDRO- l 0, lO-DIMETHYL-S-OR 9-[3-AMINO-2-OXO -OR-HYDROXY-PROPYLIDENE] 5H-DIBENZO[A,D] CYCLOHEPTENESAND- ANTHRACENES The present invention relates to new tricyclic amino compounds, to their acid addition salts and to the process for preparation thereof.

The products according to the invention have proved to be very useful in human therapeutic, namely as antidepressants and antianxiety agents.

The new tricyclic amino compounds, according to the invention, are represented by the general formula:

where X represents one of the following divalent hydrocarbon radicals:

H0 CECCHz-R (2) where X and R have the meanings defined above, or a salt of the said aminoalcohol, then by neutralizing the reaction medi' um with an alkaline agent, then by isolating the obtained compound of formula (I), where A represents a carbonyl group (C0), and eventually by reducing said compound of formula l) by gaseous hydrogen in a neutral medium and in presence of Raney nickel catalyst or by an alkali-metal borohydride, and by isolating from the reaction medium the obtained compound of formula l where A represents a hydroxymethylene group (CHOH).

The herein above described reactions can be schematized as The preferred conditions for carrying out the process are as reaction mixture and, at the completion of the reaction, the mixture is basified, for instance with a sodium hydroxide solution, and the resulting compound of formula l in which A represents a carbonyl group, is extracted by usual means. The above mentioned inorganic or organic acids may be selected advantageously from hydrochloric, sulphuric, phosphoric, formic or acetic acids.

The reduction of compound of formula (1), where A represents a carbonyl group (CO), by gaseous hydrogen in a neutral medium in the presence of Raney nickel catalyst, is carried out preferentially by stirring, under an atmosphere of hydrogen at room temperature and at atmospheric pressure, a solution of a compound of formula (I) to be reduced within a lower alkanol, such as methanol or ethanol, said solution containing a suspension of Raney nickel in the range of 5 to 20 percent in weight in respect to the weight of product to be reduced; when the reduction is complete, the catalyst is separated by filtration and the desired compound is isolated from the filtrate by usual means, for instance by concentratron.

The reduction of compound of formula (1), where A represents a carbonyl group, realized by the aid of an alkalimetal borohydride, such as sodium, potassium or lithium borohydride, is carried out preferentially by adding fractionally the alkali-metal borohydride to a solution of a compound of formula (1 to be reduced in a lower alkanol, such as methanol or ethanol, then by boiling under reflux the reaction mixture and, when the reaction is complete, by adding water and by isolating, by usual means, such as extraction and concentration, the reduced compound of fonnula (l). The alkalimetal borohydride advantageously used is sodium borohydride. The reduction by an alkali-metal borohydride can also be carried out on a salt of a compound of formula l where A represents a carbonyl group (CO).

Compounds of the above mentioned general formula (1) are basically active substances and, according to the invention, their acid addition salts can be prepared by reacting corresponding organic or inorganic acids with these compounds of formula l performing advantageously the reaction within a solvent. The preferred solvents are anhydrous solvents such as benzene, ethyl ether, ethanol and acetone. Salts can be prepared without isolating the compound of formula 1) from the reaction mixture wherein it was obtained.

According to an alternative method of the process of the invention, it is possible to obtain salts of compounds of formula (1), where A represents a carbonyl group (CO), by reacting an acetylenic aminoalcohol of formula C2) with an acid and isolating directly the acid salt of the compound of formula l where A represents a carbonyl group (CO).

The acetylenic aminoalcohol compounds of formula (2), that are used as starting materials in the foregoing procedure, can be prepared by reacting the metal salt of an acetylenic compound of general formula Me-C E C--CH R (3) where R has the meanings defined above and Me means an alkali-metal atom such as sodium, or lithium, with a ketone of general formula 0Q ii formula l-l C I C Cll R, where R has the meanings already defined, with a suitable alkaline agent, such as metalic sodium, sodium amide or lithium amide, or by reacting, in situ, an ethylenic compound of formula Hal where R has the meanings defined above and Hal means a chlorine or bromine atom, with twice the equivalent quantity of sodium or lithium amide, performing the reaction within liquid ammonia.

Tricyclic amino compounds of formula (1) and their salts are very useful substances for human therapeutic, namely because of their remarkable antidepressant and antianxiety activity.

The activity of the following compounds was studied in greater detail 10,1 1-Dihydro-5-[ 3-(dimethylamino)-2-oxo propylidene]- H- dibenzo[a,d]cycloheptene hydrochloride (hereinafter referred as 2203-01) 9,1010-Dihydro-10,10-dimethyl-9-[3-(dimethylamino)-2- oxo propy-lidene]anthracene hydrochloride (hereinafter referred as 2203-02) 10,1 l-Dihydro-5-[3-( dimethylamino )-2-hydroxy propylidene -5 l-l-dibenzo[ a,d ]cycloheptene hydrochloride (hereinafter referred as 2203-03) 10,1 l-Dihydro-5-[ 3-( methylamino )-2-oxo propylidene 5 l-l-di-benzo a,d cycloheptene hydrochloride (hereinafter referred as 2203-07) 10,1 l-Dihydro-5-[ 3-( methylamino )-2-hydroxy propylidene ]-5l-l-dibenzo a,d cycloheptene hydrochloride (hereinafter referred as 2203-08) 5-[ 3-( Dimethylamino)-2-oxo propylidene]-5H-dibenzo[ a,d]cycloheptene hydrochloride (hereinafter referred as 2203-09).

Pharmacological tests and their results were as follows:

1 Antagonism against ptosis induced in mice by injection of 0.5 mg/kg of reserpine was studied, tested compounds and reserpine being administered by intraperitoneal route simultaneously. Minimal effective doses of these compounds are indicated in the table below.

2. Antagonism of the 6 compounds against bradychardia, induced in rats by intraperitoneal injection of 5 mg of reserpine, was tested according to Halliwell et al.s method (Brit. J. Pharmacol. 1964, 23, 332), this antagonism occured from an intraperitoneal injection of 20 mg/kg. Compounds 2203-02 and 2203-08 showed the most activity.

3. Protection from electrochoc effects was evaluated on mice stereotyped 30 minutes after intraperitoneal administration of the compounds. Minimal effective doses are reported in the table below.

4. Potentiating effects of these compounds towards apomorphine were tested according to Ther and Schramms method (Arch.inter. pharmacodyn. 1962, I38, 302). Compounds by intraperitoneal route and 10 mg/kg of apomorphine hydrochloride by subcutaneous route were injected simultaneously. A visible increase of gnawing of animals was watched, that is a characteristical response of antidepressant activity ac cording to Ther (Method in drug evaluation Mantegazza and F. Piccini Ed. North Holland Publishing Company Amsterdam 1966, p. 201/2). The terminal effective doses ofthe compounds are represented in the table below.

5. Potentiation towards Sterotyped behavior induced in rats by intraperitoneal administration of 5 mg/kg of damphetamine was studied according to Halliwell et al.s technic (Brit. J. Pharmacol. 1964, 23, 330). d-Amphetamine was injected to animals 1 hour after the tested compound. A distinct increase of the stereotyped movements was observed from the doses indicated in the table.

6. Potentiating activity of the compounds towards a dose of 25 mg/kg of sodium pentobarbital was studied on mice by injecting this substance intraperitoneously 30 minutes after the compounds. The effective threshold doses are reported in the table below.

7. Lethal doses 50 (LD 50) of the compounds administered by intraperitoneal route on mice were evaluated. Death rate was noticed 48 hours after the injection and LD 50 doses were calculated according to Behrens and Karbers method.

TABLE Minimal effective doses (mg/kg) Owing to their very interesting pharmacological activities, compounds of formula (1) and their acid addition salts are very useful medicines for human therapeutic, especially as antidepressants and antianxiety agents. They can thereby be employed in treatment of depressive illness, of tempered disorders and of neurovegetative disturbances. The usual dose varies according to the utilized product, the treated patient, the concerned complaint and the selected administration route; it may be for instance from 10 mg to 200 mg per day, by oral route in human beings.

As medicines, new tricyclic amino compounds of general formula (1) according to the invention may be employed either in the form of bases or in the form of pharrnaceutically acceptable acid addition salts. Preference is given among the acid addition salts to those obtained with the following acids hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, maleic, fumaric, succinic, tartaric, citric, benzoic, alkane sulfonics, cyclohexyl sulfamic and arene sulfonics.

The present invention concerns also pharmaceutical compositions which comprise as active principles one at least of the compounds of the general formula (1) and/or their acid addition salts. These compositions are prepared in order to be administered through digestive or parenteral route. They can be solid or liquid; the pharmaceutical compositions are Those usually employed in human medicine, as for example tablets, coated or not, capsules, solutions, suppositories, parenteral preparations. They are prepared according to usual means. The active principle or principles can be incorporated with excipients which are normally employed in those pharmaceutical compositions, such as for instance, talcum, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles, various wetting dispersing and emulsifying agents and preservatives.

The following non limiting examples illustrate the invention:

EXAMPLE 1 propyl-idene C., the resulting crystals were collected and recrystallized from a mixture of ethanol and ethyl ether to give 31 g (85 percent) of 10,11-dihydro-5-[3-(dimethylamino)-2-oxo propylidene]-5l-1-dibenzo [a,d]cycloheptene hydrochloride as creamy crystals. Melting point 190 196 C. on a hot stage microscope. Analysis: C 1'1 C1 N O C H N Cl Calculated %73.3 6.8 4.3 10.8 Found %73.1 6.8 4.1 10.6

EXAMPLE 2 Calculated 7773.8 Found %73.9

9,10-Dihydro-10,lO-dimethyl-9-[3-(dimethylamino)-lpropynyl]-9-anthrol, starting material for the preparation of the above mentioned compound, was obtained as follows a solution of 32.8 g (0.2 mole) of 2-bromo-N,N-dimethyl allylamine in 20 ml of anhydrous ether was added dropwise to a suspension of sodium amide, prepared from 9.2 g (0.4 at-g) of sodium in 300 ml of liquid ammonia. Ammonia was driven off while introducing 300 ml of toluene into the reaction mixture, and a solution of 22.2 g (0.1 mole) of 10,10-dimethyl anthrone in 100 ml of toluene was added. The mixture was boiled under reflux for 6 hours, while stirring. After cooling, 200 ml of water were added, dropwise. The resulting precipitate was collected, dried and recrystallized from 800 ml of methanol to give 17.8 g (58.5 percent) of 9,10-dihydro- 10,10-dimethyl-9-[3-(dimethylamino)-l-propynyl]-9- anthrol. Melting point 204 205 C. on a hot stage microscope. Analysis C H N O C H N Calculated %826 7.6 4.6 Found %82.7 7.7 4.6

EXAMPLE 3 10,1 1-Dihydro5-[3-(dimethylamino)-2-hydroxy propylidene]-5H-dibenzo[a,d]cycloheptene hydrochloride.

A solution of 5.8 g (0.02 mole) of 10,11-dihydro-5- [3- (dimethylamino)-2-oxo propylidene]-5H-dibenzo[a,d]cycloheptene in 100 ml of ethanol, containing 1 g of Raney nickel in suspension, was stirred under hydrogen at atmospheric pressure and room temperature. When the theoretical quantity of hydrogen was absorbed, the catalyst was separated by filtration, and the filtrate was treated with dry hydrochloric acid. Ethanol was driven off by concentration in vacuo, and the solid residue was recrystallized from a mixture of acetone and ether to give 5.35 g (81 percent) of 10,1 l-dihydro-5-[3- (dimethylamino )-2-hydroxy propylidene ]-5l-l-dibenzo[ a,d]cycloheptene hydrochloride. Melting point 206 C. on a hot stage microscope.

Analysis C H Cl N O Calculated 1672.8 Found 1672.6

EXAMPLE 4 10, 1 1-Dihydro-5-[3-(dimethylamino)-2-hydroxy lidene]-5H-dibenzo[a,d]cycloheptene hydrochloride.

Solid sodium borohydride (3.8 g, 0.1 mole) was added in small portions to a stirred solution of 6.6 g (0.02 mole) of 10,1 l-dihydro-5-[ 3-( dimethylamino )-2-oxo propylidene ]-5H- dibenzo[a,d]cycloheptene hydrochloride in ml of methanol. Stirring was carried on during 1 hour at room temperature, then 1 hour under reflux at boiling temperature. After cooling, ml of water were added, and methanol was driven off in vacuo. The resulting aqueous solution was extracted several times with ether. Ethereal extracts were col-' lected, dried and treated with dry hydrochloric acid. Ether was driven off by concentration, and the residue was recovered in 80 ml of acetone. By adding ether to this solution, there was obtained a precipitate which was recrystallized from a mixture of acetone and ether to give 3 g (50 percent) of 10,1l-dihydro-5-[3-di-methylamino)-2-hydroxy propylidene]-5H-dibenzo[a,d]cyc1oheptene hydrochloride, identical to the compound prepared in Example 3. Melting point 205 206 C. on a hot stage microscope.

EXAMPLE 5 propyli-dene ]-5- Calculated %72.7 Found %72.7

EXAMPLE 6 10,1 lDihydro-5-[ 3-( methylamino )-2-hydroxy propylidene 5H-dibenzo[a,d]cycloheptene hydrochloride.

Solid sodium borohydride (1.9 g, 0.05 mole) was added in small portions to a stirred suspension of 3.1 g (0.01 mole) of 10,1 l-dihydro-5-3-(methylamino )-2-oxo propylidene1-5H-dibenzo[a,d]cycloheptene hydrochloride in 40 ml of methanol. The mixture was stirred continuously during 1 hour at room temperature, then during 1 hour under reflux at boiling temperature. After cooling, 50 ml of water were added, methanol was driven off in vacuo. The aqueous solution was extracted several times with ether. Ethereal extracts were collected, dried and treated with dry hydrochloric acid. The resulting precipitate was recrystallized from a mixture of acetone and ether to give 2.4 g (76 percent) of 10,1 1-dihydro-5-[3- (methylamino)-2hydroxy propylidene]-5H-bibenzo[ a,d]cycloheptene hydrochloride as white crystals. Melting point 171 174 C. on a hot stage microscope.

Analysis C H Cl N O C H Calculated %72.3 7.0 Found %72.0 7.0

EXAMPLE 7 propylidene ]-51-1-di-benzo[ mixture of acetone, ethanol and ether, 4.7 g (72 percent) of [3-( dimethylamino)-2-oxo propylidene ]-5H-dibenzo [a,d lcycloheptene hydrochloride as creamy crystals. Melting point 180 183 C. on a hot stage microscope.

Analysis C H Cl N O C H Cl Calculated %73.7 6.2 10.9 Found %73.3 6.6 10.2

5-[ 3-( Dimethylamino)- l -propynyl]-5 H-dibenzo[ a,d]cycloheptene5-ol, starting material for the preparation of the above mentioned compound, was obtained as follows 29.9 g (0.25 mole) of 2-chloro-N,N-dimethyl allylamine were added dropwise to a suspension of sodium amide prepared from l 1.5 g (0.5 at-g) of sodium in 500 ml of liquid ammonia. The reaction mixture was stirred during 1 hour, and a solution of 50 g (0.242 mole) of 5H-dibenzo[a,d]cycloheptene-5-one in 200 ml of anhydrous xylene was introduced dropwise. Stirring was prosecuted until the whole excess of ammonia was removed, and 200 m1 of water were added dropwise. The resulting precipitate was collected and dried to give 36.5 g (52 percent) of 5-[3-(dimethyl-amino l -propynyl]-5H-dibenzo[ a,d]c ycloheptene-S-ol as white crystals. Melting point 176 178 C. on a hot stage microscope after recrystallization from a mixture of benzene and petrol ether.

Analysis: C H N O Calculated %83.0 Found %83.3

EXAMPLE 8 Tablets were prepared which corresponded to the formula 20 mg 200 mg EXAMPLE 9 Tablets were prepared which corresponded to the formula:

'1, l h-Dihydrrr l 0, l 0-dimethyl-9-I 3- rdimethylamino)2-oxo propylidenejanthracene hydrochloride 20 mg Excipient s.q. for 1 tablet 200 mg (Excipient: lactose, starch, talcum,

magnesium stearate).

EXAMPLE 10 Tablets were prepared which corresponded to the formula:

l0,l l-Dihydro-5-[3-(dimethylamino)-2- hydroxy propylidene]-5H-dibenzo[ a,d]cycloheptene hydrochloride Excipient s.q. for 1 tablet (Excipient lactose, starch, talcum magnesium stearate).

EXAMPLE l 1 Tablets were prepared which corresponded to the formula:

20 mg 200 mg 5[3-(Dimethylamino)-2-oxo propylidene1-Sl-ldibenzo[a,d]cycloheptene hydrochloride Excipient s.q. for 1 tablet (Excipient: lactose, starch talcum,

magnesium, stearate).

EXAMPLE 1 2 A parenteral preparation was prepared which corresponded to the formula:

20 mg 200 mg l0,l l-Dihydro-5-[3-(dimethylamino)-2-oxo propylidene]-5H-dibenzo[a,d]cycloheptene hydrochloride Aqueous solvent 20 mg 2 ml We claim:

1. A compound selected from the group consisting of tricyclic amino compounds and acid addition salts thereof, said tricyclic amino compounds having the general formula A is a member selected from the group consisting of carbonyl (CO) and hydroxymethylene (CHOH) radicals and R is a member selected from the group consisting of monoalkylamino and dialkylamino radicals.

2. A compound selected from the group consisting of l0,l ldihydro-5-[3-(dimethylamino)-2-oxo propylidene1-5H- dibenzo [a,d] cycloheptene and acid addition salts thereof.

3. A compound selected from the group consisting of 9,10- dihydro-l0,lO-dimethyl-9-[3-(dimethylamino)-2-oxo propylidene] anthracene and acid addition salts thereof.

4. A compound selected from the group consisting of 10,1 1- dihydro-5[3-(dimethylamino)-2-hydroxy propylidene]-5l-ldibenzo [a,d]cycloheptene and acid addition salts thereof.

5. A compound selected from the group consisting of 5-[ 3- (dimethylamino )-2-oxo propylidene ]-5H-dibenzo [a,d]cycloheptene and acid addition salts thereof. 

2. A compound selected from the group consisting of 10,11-dihydro-5-(3-(dimethylamino)-2-oxo propylidene)-5H-dibenzo (a,d) cycloheptene and acid addition salts thereof.
 3. A compound selected from the group consisting of 9,10-dihydro-10,10-dimethyl-9-(3-(dimethylamino)-2-oxo propylidene) anthracene and acid addition salts thereof.
 4. A compound selected from the group consisting of 10,11-dihydro-5-(3-(dimethylamino)-2-hydroxy propylidene)-5H-dibenzo (a,d)cycloheptene and acid addition salts thereof.
 5. A compound selected from the group consisting of 5-(3-(dimethylamino)-2-oxo propylidene)-5H-dibenzo (a,d)cycloheptene and acid addition salts thereof. 